Explore the vast range of titles available.

Interaction between tumor cells and immune cells in the tumor microenvironment is important in cancer development. Immune cells interact with the tumor cells to shape this process. Here, we use single-cell RNA sequencing analysis to delineate the immune landscape and tumor heterogeneity in a cohort of patients with HBV-associated human hepatocellular carcinoma (HCC). We found that tumor-associated macrophages suppress tumor T cell infiltration and TIGIT-NECTIN2 interaction regulates the immunosuppressive environment. The cell state transition of immune cells towards a more immunosuppressive and exhaustive status exemplifies the overall cancer-promoting immunocellular landscape. Furthermore, the heterogeneity of global molecular profiles reveals co-existence of intra-tumoral and inter-tumoral heterogeneity, but is more apparent in the latter. This analysis of the immunosuppressive landscape and intercellular interactions provides mechanistic information for the design of efficacious immune-oncology treatments in hepatocellular carcinoma. Different cells of the tumour microenvironment in HBV-associated human hepatocellular carcinoma (HCC) interact to promote tumour immunity. Here the authors use single cell RNA sequencing to identify TIGIT-NECTIN2 as a pathway by which tumour-associated macrophages reduce intratumour T cell activation.

There is an interesting and long history of prostheses designed for those with upper-limb difference, and yet issues still persist that have not yet been solved. Prosthesis needs for children are particularly complex, due in part to their growth rates. Access to a device can have a significant impact on a child’s psychosocial development. Often, devices supporting both cosmetic form and user function are not accessible to children due to high costs, insurance policies, medical availability, and their perceived durability and complexity of control. These challenges have encouraged a grassroots effort globally to offer a viable solution for the millions of people living with limb difference around the world. The innovative application of 3D printing for customizable and user-specific hardware has led to open-source Do It Yourself “DIY” production of assistive devices, having an incredible impact globally for families with little recourse. This paper examines new research and development of prostheses by the maker community and nonprofit organizations, as well as a novel case study exploring the development of technology and the training methods available. These design efforts are discussed further in the context of the medical regulatory framework in the United States and highlight new associated clinical studies designed to measure the quality of life impact of such devices.

This study aims to investigate the association of pre-treatment multi-phasic MR-based radiomics and dosimetric features with treatment response to a novel sequential trans-arterial chemoembolization (TACE) plus stereotactic body radiotherapy (SBRT) plus immunotherapy regimen in unresectable Hepatocellular Carcinoma (HCC) sub-population. Twenty-six patients with unresectable HCC were retrospectively analyzed. Radiomic features were extracted from 42 lesions on arterial phase (AP) and portal-venous phase (PVP) MR images. Delta-phase (DeltaP) radiomic features were calculated as AP-to-PVP ratio. Dosimetric data of the tumor was extracted from dose-volume-histograms. A two-sided independent Mann–Whitney U test was used to assess the clinical association of each feature, and the classification performance of each significant independent feature was assessed using logistic regression. For the 3-month timepoint, four DeltaP-derived radiomics that characterize the temporal change in intratumoral randomness and uniformity were the only contributors to the treatment response association (p-value = 0.038–0.063, AUC = 0.690–0.766). For the 6-month timepoint, DeltaP-derived radiomic features (n = 4) maintained strong clinical associations with the treatment response (p-value = 0.047–0.070, AUC = 0.699–0.788), additional AP-derived radiomic features (n = 4) that reflect baseline tumoral arterial-enhanced signal pattern and tumor morphology (n = 1) that denotes initial tumor burden were shown to have strong associations with treatment response (p-value = 0.028–0.074, AUC = 0.719–0.773). This pilot study successfully demonstrated associations of pre-treatment multi-phasic MR-based radiomics with tumor response to the novel treatment regimen.

BackgroundNon-alcoholic fatty liver disease (NAFLD) is increasingly recognized as a risk for hepatocellular carcinoma (HCC). The core of NAFLD pathogenesis is primarily associated with dysregulated lipid metabolism, which leads to lipid accumulation within hepatocytes. It not only contributes to lipotoxicity as a potential oncogenic evolution towards HCC, but also underpins immune evasion within the tumor microenvironment. Recent studies have identified the elongation of fatty acids, predominantly mediated by the ELOVL family of enzymes, as a contributing factor in the progression of NAFLD. Nevertheless, the implications of ELOVL activity in the transition from NAFLD to HCC are not yet fully elucidated.MethodsMouse CRISPR/dCas9-mediated transcriptional activation library screening systems were applied to determine the key targets in the progression of NAFLD-HCC in mouse models. RNA-sequencing analysis were used to explore the crucial signalling pathway. A comprehensive analysis of ELOVL1 expression in the NAFLD-HCC local cohort were performed. DEN or transgenic TP53KO/MycOE mouse with high-fat methionine-choline-deficient diet (HFMCD) induced NAFLD-HCC model were established to explore the role of ELOVL1 on tumor progression.ResultsELOVL1 was a top candidate in the NAFLD-HCC orthotopic mouse model among fatty acid elongation family by CRISPR-dCas9 screening. RNA-seq data and local clinical samples showed that ELOVL1 expression was significantly induced in NAFLD-HCC (IDDF2024-ABS-0199-Figure 1. ELOVL1 was upregulated in NAFLD HCC and crucial for NAFLD HCC progression in vivo). The increased expression of ELOVL1 was correlated with poor overall survival (OS) and less CD8+ T cells infiltration in the local cohort (IDDF2024-ABS-0199 Figure 2. ELOVL1 was overexpressed in NAFLD HCC with poor clinical features and less CD8 T cells infiltration). ELOVL1 knockdown could inhibit HCC growth in HFMCD-induced NAFLD-HCC models and alleviate the fibrosis level in the liver context (IDDF2024-ABS-0199 Figure 3. ELOVL1 knockdown inhibited HCC growth in HFMCD-induced NAFLD HCC models). ELOVL1 knockdown inhibited hepatocarcinogenesis and reshaped immune cells infiltration profile with less CD206+IL10+ mφ and more TNF-α/IFN-γ CD8+ T cells infiltration (IDDF2024-ABS-0199 Figure 4. ELOVL1 knockdown inhibited hepatocarcinogenesis and reshaped immune cells infiltration profile). Cell sorting and RNA-seq demonstrated that GPNMB+ mφ infiltration was the main cause of ELOVL1-promoting tumor growth (IDDF2024-ABS-0199 Figure 5. GPNMB macrophages infiltration accounted for ELOVL1-promoting tumor growth).ConclusionsELOVL1 reshapes the immune cell profile in the tumor microenvironment with a high infiltration of GPNMB+ M2-like macrophages, which may diminish CD8+ T cell anti-tumor immunity and accelerate NAFLD-HCC progression.Abstract IDDF2024-ABS-0199 Figure 1ELOVL1 was upregulated in NAFLD HCC and crucial for NAFLD HCC progression in vivoAbstract IDDF2024-ABS-0199 Figure 2ELOVL1 was overexpressed in NAFLD HCC with poor clinical features and less CD8 T cells infiltrationAbstract IDDF2024-ABS-0199 Figure 3ELOVL1 knockdown inhibited HCC growth in HFMCD-induced NAFLD HCC modelsAbstract IDDF2024-ABS-0199 Figure 4ELOVL1 knockdown inhibited hepatocarcinogenesis and reshaped immune cells infiltration profileAbstract IDDF2024-ABS-0199 Figure 5GPNMB macrophages infiltration accounted for ELOVL1-promoting tumor growth

We present a 37 years’ experience in the management of biliary atresia (BA) and discuss long-term complications after Kasai portoenterostomy (KPE). A retrospective territory-wide study from 1980 to 2017 on 231 patients with open KPE from three tertiary paediatric surgical centres was performed. Outcome parameters were clearance of jaundice (COJ), native liver survival (NLS) and long-term complications. Factors affecting the operative outcomes were analyzed. The median duration of follow up was 17.5 (IQR: 13.5–22) years. Over 66% of patients became jaundice-freed at 1 year after KPE. Seventy patients (30.3%) received liver transplant (LT) at a median age of 6.2 (IQR: 4.3–8.4) years. The NLS rates at 10 and 20 years were 70.7% and 61.5% respectively with no significant change over the study period. The median age at KPE was 59 (IQR: 49–67) days. KPE performed before 70 days was associated with higher odd ratios for successful drainage but the age of KPE did not have an impact on the long-term NLS. Among all native liver survivors (n = 153), the median bilirubin level was 24 (IQR: 16–36) µmol/L. Portal hypertension (PHT) and recurrent cholangitis were found in 51.6% and 27.5% of them respectively. With a vigilant follow up program, more than 60% of BA patients could remain stable with the disease and achieve long-term survival without LT. Although cholestasis, portal hypertension and recurrent cholangitis are common in long-term NLS, with a comprehensive follow management strategy, they do not always necessitate LT. Our study serves as an example for countries where deceased donor organs are scarce due to very low donation rate.

BackgroundFerroptosis is a form of regulated cell death caused by an iron-dependent accumulation of lipid peroxides. Tumor-infiltrating CD8+T cells are associated with progressive loss of effector function due to a suppressive tumor microenvironment (TME). In the TME, tumors cells may cause CD8+T cells dysfunction by secreting various bioactive substances, including exosomes. Yet, the role of tumor-derived exosomes (TDEs) in regulating ferroptosis of CD8+T cells is still unexplored and remains enigmatic.MethodsThe gene and protein expressions of ferritin heavy chain 1(FTH1) in hepatocellular carcinoma (HCC) tissues were investigated in our clinical cohort as well as in HCC cell lines. Flow cytometry and multiplex immunostaining were used to characterize ferroptosis of CD8+T cells. T cells were isolated and cultured with TDEs in vitro for functional experiments. Mouse liver tumor models were applied to assess the role of ferroptosis inhibition in the improvement of anti-tumor immunity in vivo.ResultsClinically, we demonstrated that FTH1 expression was upregulated in HCC tissues and negatively correlated with the overall survival and clinicopathological scores (IDDF2022-ABS-0176 Figure 1A-C. TfR+CD8+T cells within FTH1 expression tumor tissues indicate poor prognosis of HCC). Specifically, high expression of FTH1 is positively associated with the cluster of ferroptosis CD8+T cells abundant within HCC tissues (IDDF2022-ABS-0176 Figure 1D-E. TfR+CD8+T cells within FTH1 expression tumor tissues indicate poor prognosis of HCC). In in vitro experiments, FTH1 was found highly expressed in exosomes of HCC cell lines. TDEs mediated uptake of FTH1 by CD8+T cells induced lipid peroxidation and ferroptosis (IDDF2022-ABS-0176 Figure 2A-B. Tumor derived exosomes can be taking up by CD8+T cells), subsequently impaired the cytotoxic functions of CD8+T cells and aggravated CD8+T cell exhaustion status (IDDF2022-ABS-0176 Figure 2C-D. Tumor derived exosomes can be taking up by CD8+T cells). Mechanistically, NCOA4-mediated ferritin selective autophagy (ferritinophagy) was initiated during ferritin degradation, promoting labile iron accumulation on CD8+T cells (IDDF2022-ABS-0176 Figure 3. HCC-derived exosomes mediate ferroptosis and exhaustion in human CD8+T cells). In animal models, using deferoxamine and FTH1 knockdown inhibited ferroptosis on CD8+T cells and effectively restored their anti-tumor activity in the mice model (IDDF2022-ABS-0176 Figure 4. Ferritinophagy is involved in HCC derived exosomes induced cell death) ( IDDF2022-ABS-0176 Figure 5. FTHI promotes tumor growth and CD8+T cells ferroptosis in HCC mouse model).Abstract IDDF2022-ABS-0176 Figure 1A-GTfR=CD8=T cells within FTH1 expression tumor tissues indicate poor prognosis of HCCAbstract IDDF2022-ABS-0176 Figure 2A-DTumor derived exosomes can be taking up CD8+T cellsAbstract IDDF2022-ABS-0176 Figure 3HCC-derived exosomes mediate ferroptosis and exhaustion in human CD8+T cellsAbstract IDDF2022-ABS-0176 Figure 4Ferritinophagy is involved in HCC derived exosomes induced cell deathAbstract IDDF2022-ABS-0176 Figure 5FTH1 promotes tumor growth and CD8+T cells ferroptosis in HCC mouse modelConclusionsTumor-derived exosomal FTH1 promoted CD8+ T cell ferroptosis in HCC through NCOA4-mediated ferritinophagy, highlighting a promising strategy for cancer immunotherapy.

Chimeric antigen receptor T cell (CAR-T) therapy is novel tumor immunotherapy that enables autologous T to express synthetic receptors to specifically recognize the surface tumor-associated antigens for exerting subsequent antitumor effects, and eliminating the resistance, metastases and recurrence of cancer. Although CAR T cells have exhibited success in eradicating hematologic malignancies, their applications to solid tumors has not yet been achieved due to obstacles such as the immune-suppressor tumor microenvironment and lack of tumor specific target antigens. In this review, we presented advancements in the development of CAR T cell therapy in solid tumors, and offered a brief summary of the challenges, as well as novel engineering and pharmaceutical interventions to overcome these barriers. Looking forward, we discussed the latest studies which are expected to reach the clinicals in the next few years, including CRISPR screens-based CAR modification and CAR T cells driven from progenitor-like T cells. Collectively, this review may inspire researchers and clinicians to develop clinical available strategies of CAR T cell therapies in solid tumor.

The long-term outcomes of oral antiviral therapy without hepatitis B immune globulin (HBIG) in prevention of reinfection with hepatitis B after liver transplantation are not known. We aimed to determine the long-term outcomes from a large population of chronic hepatitis B (CHB) liver transplant recipients using oral antiviral therapy alone. A total of 362 consecutive CHB patients transplanted from January 2003 to May 2011 were included. None of the patients received HBIG. Viral serology, viral load, and liver biochemistry were performed at regular intervals during follow-up. Of the 362 patients, 176 (49%), 142 (39%), and 44 (12%) were on lamivudine (LAM), entecavir (ETV), and combination therapy (predominantly LAM+adefovir), respectively, at the time of transplant. The median follow-up length was 53 months. The rate of hepatitis B surface antigen seronegativity and hepatitis B virus (HBV) DNA suppression to undetectable levels at 8 years was 88 and 98%, respectively. The virological relapse rates (>1 log increase IU/ml) at 1, 3, 5, and 8 years was 5, 10, 13 and 16%, respectively. The virological relapse rate at 3 years for LAM, ETV, and combination group was 17, 0, and 7%, respectively (P<0.001). Forty-two patients had virological relapse, of which 36 had YMDD mutation (31 in the LAM group and 5 in the combination group). The overall 8-year survival was 83%, with no difference between the three treatment groups (P=0.94). No mortality from HBV recurrence occurred in the 362 patients. Oral nucleoside/nucleotide analogs without HBIG are effective in preventing graft loss secondary to hepatitis B recurrence after liver transplantation. However, new agents with a high barrier to resistance should be used to minimize drug resistance and to prevent virological rebound.

Patients receiving total intravenous anesthesia (TIVA) with propofol have been shown to experience less postoperative pain. We evaluated the post-operative analgesic effects of propofol compared with sevoflurane maintenance of anesthesia in liver surgery. This study was registered at ClinicalTrials.gov (NCT02179437). In this retrospective study, records of patients who underwent liver surgery between 2010 and 2013 were reviewed. Ninety-five patients anesthetized with propofol TIVA were matched with 95 patients anesthetized with sevoflurane. Numeric pain rating scale (NRS) pain scores, postoperative morphine consumption, side effects and patients' satisfaction with pain relief were evaluated. The TIVA group reported lower NRS pain scores during coughing on postoperative days 1 and 2 but not 3 (p = 0.0127, p = 0.0472, p = 0.4556 respectively). They also consumed significantly less daily (p = 0.001 on day 1, p = 0.0231 on day 2, p = 0.0004 on day 3), accumulative (p = 0.001 on day 1, p<0.0001 on day 2 and p = 0.0064 on day 3) and total morphine (p = 0.03) when compared with the sevoflurane group. There were no differences in total duration of intravenous patient controlled analgesia (PCA) morphine use and patient satisfaction. No difference was found in reported side effects. Patients anesthetized with propofol TIVA reported less pain during coughing and consumed less daily, accumulative and total morphine after liver surgery.